System and method for performing renal denervation verification

ABSTRACT

A renal denervation feedback method is described that performs a baseline measurement of renal nerve plexus electrical activity at a renal vessel; denervates at least some tissue proximate the renal vessel after performing the baseline measurement; performs a post-denervation measurement of renal nerve plexus electrical activity at the renal vessel, after the denervating; and assesses denervation of the renal vessel based on a comparison of the baseline measurement and the post-denervation measurement of renal nerve plexus electrical activity at the renal vessel.

BACKGROUND OF THE INVENTION

The present invention relates generally to denervation, and morespecifically to systems and methods for renal denervation verificationand feedback.

Hypertension (HTN), or high blood pressure (HBP), is defined as aconsistently elevated blood pressure (BP) greater than or equal to 140mmHg systolic blood pressure (SBP) and 90 mmHg diastolic blood pressure(DBP). Hypertension is a “silent killer” that is not associated with anysymptoms and in 95% of cases (primary hypertension) the specific causeis unknown. In the remaining 5% of patients (secondary hypertension),specific causes including chronic kidney disease, diseases of theadrenal gland, coarctation of the aorta, thyroid dysfunction, alcoholaddiction, pregnancy or the use of birth control pills are present. Insecondary hypertension, when the root cause is treated, blood pressureusually returns to normal.

Hypertension is a disease that affects 74.5 million patients in the USwith 24% or 17.7 million patients classified as uncontrolledhypertensive patients. Of these 17.7 million US patients, 27% of themare resistant to drug therapy without any secondary causes. This equatesto 4.8 million patients in the US and an estimated 12.4 million patientsoutside of the US for a total of 17.2 million patients worldwide.Needless to say, there is a need for additional therapeutic options forthis class of unsuccessfully treated patients.

It is generally accepted that the causes of hypertension aremulti-factorial, with a significant factor being the chronichyper-activation of the sympathetic nervous system (SNS), especially therenal sympathetic nerves. Renal sympathetic efferent and afferentnerves, which lie in the wall of the renal artery, have been recognizedas a critical factor in the initiation and maintenance of systemichypertension. Renal arteries, like all major blood vessels, areinnervated by perivascular sympathetic nerves that traverse the lengthof the arteries. The perivascular nerves consist of a network of axons,terminals, and varicosities, which are distributed mostly in themedial-adventitial and adventitial layers of the arterial wall.

Signals coming in to the kidney travel along efferent nerve pathways andinfluence renal blood flow, trigger fluid retention, and activate therenin-angiotensin-aldosterone system cascade. Renin is a precursor tothe production of angiotensin II, which is a potent vasoconstrictor,while aldosterone regulates how the kidneys process and retain sodium.All of these mechanisms serve to increase blood pressure. Signals comingout of the kidney travel along afferent nerve pathways integrated withinthe central nervous system, and lead to increased systemic sympatheticnerve activation. Chronic over-activation can result in vascular andmyocardial hypertrophy and insulin resistance, causing heart failure andkidney disease.

Previous clinical studies have documented that denervating the kidneyhas a positive effect for both hypertension and heart failure patients.Journal articles published as early as 1936 review surgical procedurescalled either sympathectomy or splanchnicectomy, to treat severehypertension. A 1953 JAMA article by Smithwick et al. presented theresults of 1,266 cases of surgical denervation to treat hypertension.The results included radiographic evidence of hearts that had remodeledafter the surgery, while also showing significant blood pressuredeclines. Additional articles published in 1955 and 1964 demonstratedthat the concept of using renal denervation to lower blood pressure andtreat heart failure was viable. However, given the highly invasive andtraumatic nature of the procedure and the advent of more effectiveantihypertensive agents, the procedure was not widely employed.

More recently, catheter ablation has been used for renal sympatheticdenervation. Renal denervation is a method whereby amplified sympatheticactivities are suppressed to treat hypertension or other cardiovasculardisorders and chronic renal diseases. The objective of renal denervationis to neutralize the effect of renal sympathetic system which isinvolved in arterial hypertension. The renal sympathetic efferent andafferent nerves lie within and immediately adjacent to the wall of therenal artery. Energy is delivered via a catheter to ablate the renalnerves in the right and left renal arteries in order to disrupt thechronic activation process. As expected, early results appear both toconfirm the important role of renal sympathetic nerves in resistanthypertension and to suggest that renal sympathetic denervation could beof therapeutic benefit in this patient population.

In clinical studies, therapeutic renal sympathetic denervation hasproduced predictable, significant, and sustained reductions in bloodpressure in patients with resistant hypertension. Catheters areflexible, tubular devices that are widely used by physicians performingmedical procedures to gain access into interior regions of the body. Acatheter device can be used for ablating renal sympathetic nerves intherapeutic renal sympathetic denervation to achieve reductions of bloodpressure in patients suffering from renal sympathetic hyperactivityassociated with hypertension and its progression. Renal artery ablationfor afferent and efferent denervation has been shown to substantiallyreduce hypertension. See, e.g., Henry Krum et al., “Catheter-based renalsympathetic denervation for resistant hypertension: a multicentre safetyand proof-of-principle cohort study,” published online Mar. 30, 2009 atwww.thelancet.com. Krum et al. recently reported average reductions of27 mmHg SBP and 13 mmHg DBP in 34 patients with 12-month follow-up data.In addition, despite having an average SBP baseline of 177 mmHg, 44% ofthose patients reached controlled blood pressure of <140 mmHg.

SUMMARY

Embodiments of this invention provide renal denervation validation andfeedback by detecting renal nerve activity and/or the lack thereof inorder to precisely titrate the RF energy dose to achieve the desiredrenal denervation. The use of RF ablation for denervation is merelyillustrative in this disclosure. Other denervation techniques can beused instead, as discussed below.

The first approach assesses the completeness of the renal denervationsuch as renal artery ablation by measuring the renal nerve plexuselectrical activity on the distal side of the lesion site. This activitywill be solely intrinsic since there is no external stimulation of therenal nerve plexus. The second approach assesses the completeness of therenal artery ablation by stimulating the renal nerve plexus on theproximal side of the lesion while recording the renal nerve plexusactivity on the distal side of the lesion, or vice versa. The thirdapproach verifies with a high degree of confidence that efferent andafferent renal artery nerves have been disconnected. This isaccomplished by applying stimulus at a first position in a renal arteryand verifying that nerve conduction has been interrupted by evaluating afiltered, detected signal at a second position, and then repeating theprocedure with stimulation and detection positions swapped. Theseapproaches are illustrative but not limiting.

Embodiments of the present invention provide a feedback mechanism tocontrol renal denervation (e.g., to titrate RF energy delivery for renalablation). By assessing the denervation after ablation based on abaseline measurement, one can prevent excessive, unnecessary ablation ordenervation. The denervation verification increases the response rate byensuring that the renal nerve plexus is completely destroyed or at leastadequately destroyed based on a preset threshold.

In accordance with an aspect of the present invention, a renaldenervation feedback method comprises: performing a baseline measurementof renal nerve plexus electrical activity at a renal vessel; denervatingat least some tissue proximate the renal vessel after performing thebaseline measurement; performing a post-denervation measurement of renalnerve plexus electrical activity at the renal vessel, after thedenervating; and assessing denervation of the renal vessel based on acomparison of the baseline measurement and the post-denervationmeasurement of renal nerve plexus electrical activity at the renalvessel.

In some embodiments, the method further comprises, if a targetdenervation of the renal vessel is not achieved, repeating the steps ofdenervating, performing a post-denervation measurement, and assessingdenervation of the renal vessel until the target denervation of therenal vessel is achieved. Repeating the steps of denervating, performinga post-denervation measurement, and assessing denervation of the renalvessel comprises adjusting a level of denervation for denervating atleast some tissue proximate the renal vessel based on result ofassessing denervation of the renal vessel.

In specific embodiments, performing a baseline measurement comprisesmonitoring baseline afferent signals and baseline efferent signals atthe renal vessel without external stimulation to the renal vessel, andperforming a post-denervation measurement comprises monitoringpost-denervation afferent signals and post-denervation efferent signalsat the renal vessel without external stimulation to the renal vessel,after the denervating. Monitoring the baseline afferent signals andbaseline efferent signals comprises monitoring baseline afferentcompound action potential and baseline efferent compound actionpotential, counting a number of baseline afferent spikes eachrepresenting an afferent compound action potential that exceeds a presetthreshold during a specified period of time, and counting a number ofbaseline efferent spikes each representing an efferent compound actionpotential that exceeds the preset threshold during the specified periodof time. Monitoring the post-denervation afferent signals andpost-denervation efferent signals comprises monitoring post-denervationafferent compound action potential and post-denervation efferentcompound action potential, counting a number of post-denervationafferent spikes each representing an afferent compound action potentialthat exceeds the preset threshold during the specified period of time,and counting a number of post-denervation efferent spikes eachrepresenting an efferent compound action potential that exceeds thepreset threshold during the specified period of time.

In some embodiments, the baseline measurement and the post-denervationmeasurement occur at a location of the renal vessel proximal of a kidneyand proximal of a denervation location for denervating at least sometissue proximate the renal vessel, and the target denervation of therenal vessel is achieved when a ratio of the number of post-denervationafferent spikes to the number of post-denervation efferent spikes isbelow a preset threshold as compared to a ratio of the number ofbaseline afferent spikes to the number of baseline efferent spikes. Thebaseline measurement and the post-denervation measurement occur at alocation of the renal vessel proximal of a kidney and distal of adenervation location for denervating at least some tissue proximate therenal vessel, and the target denervation of the renal vessel is achievedwhen a ratio of the number of post-denervation afferent spikes to thenumber of post-denervation efferent spikes is above a preset thresholdas compared to a ratio of the number of baseline afferent spikes to thenumber of baseline efferent spikes.

In specific embodiments, performing a baseline measurement comprisessupplying nerve stimulation to the renal vessel from one side of adenervation location for denervating at least some tissue proximate therenal vessel and measuring a baseline response of the renal vessel tothe nerve stimulation on an opposite side of the denervation location,and performing a post-denervation measurement comprises supplying nervestimulation to the renal vessel from one side of the denervationlocation and measuring a post-denervation response of the renal vesselto the nerve stimulation on an opposite side of the denervationlocation. The same nerve stimulation is supplied from a same firstlocation on the same side of the denervation location for both thebaseline measurement and the post-denervation measurement, and theresponse is recorded on a same second location on the same opposite sideof the denervation location for both the baseline measurement and thepost-denervation measurement.

In some embodiments, the nerve stimulation is supplied from the proximalside of the denervation location for both the baseline measurement andthe post-denervation measurement, and the response is recorded on thedistal side of the denervation location for both the baselinemeasurement and the post-denervation measurement. The nerve stimulationcomprises one of electrical stimulation or pharmacological stimulation.Assessing denervation of the vessel comprises: computing a baselineparameter from the baseline response; computing a post-denervationparameter from the post-denervation response; and computing a degree ofdenervation as a ratio of the post-denervation parameter and thebaseline parameter. The target denervation is achieved when the computedratio falls within a preset range. The baseline parameter comprises anumber of baseline spikes each representing a compound action potentialthat exceeds a preset threshold during a specified period of time asmeasured in the baseline response. The post-denervation parametercomprises a number of post-denervation spikes each representing acompound action potential that exceeds the same preset threshold duringthe same specified period of time as measured in the post-denervationresponse. The target denervation is achieved when the computed ratiofalls below a preset number.

In specific embodiments, performing a baseline measurement comprisessupplying nerve stimulation to the renal vessel from a first side of adenervation location for denervating at least some tissue proximate therenal vessel and measuring a first baseline response of the renal vesselto the nerve stimulation on a second side of the denervation locationopposite the first side, and supplying nerve stimulation to the renalvessel from the second side and measuring a second baseline response ofthe renal vessel to the nerve stimulation on the first side, andperforming a post-denervation measurement comprises supplying nervestimulation to the renal vessel from the first side and measuring afirst post-denervation response of the renal vessel to the nervestimulation on the second side, and supplying nerve stimulation to therenal vessel from the second side and measuring a secondpost-denervation response of the renal vessel to the nerve stimulationon the first side. Performing a baseline measurement comprises supplyingnerve stimulation to the renal vessel from a first location on the firstside of the denervation location and measuring the first baselineresponse of the renal vessel to the nerve stimulation on a secondlocation on the second side, and supplying nerve stimulation to therenal vessel from the second location and measuring the second baselineresponse of the renal vessel to the nerve stimulation at the firstlocation. Performing a post-denervation measurement comprises supplyingnerve stimulation to the renal vessel from the first location andmeasuring the first post-denervation response of the renal vessel to thenerve stimulation at the second location, and supplying nervestimulation to the renal vessel from the second location and measuringthe second post-denervation response of the renal vessel to the nervestimulation at the first location.

In some embodiments, measuring the first baseline response comprisesfiltering the first baseline response to increase signal-to-noise ratio;measuring the second baseline response comprises filtering the secondbaseline response to increase signal-to-noise ratio; measuring the firstpost-denervation response comprises filtering the first baselineresponse to increase signal-to-noise ratio; and measuring the secondpost-denervation response comprises filtering the second baselineresponse to increase signal-to-noise ratio.

In specific embodiments, measuring the first baseline response comprisessynchronizing with electrocardiogram to substantially avoid detectedsignals other than detected signals that are recorded duringelectrically quiet times; measuring the second baseline responsecomprises synchronizing with electrocardiogram to substantially avoiddetected signals other than detected signals that are recorded duringelectrically quiet times; measuring the first post-denervation responsecomprises synchronizing with electrocardiogram to substantially avoiddetected signals other than detected signals that are recorded duringelectrically quiet times; and measuring the second post-denervationresponse comprises synchronizing with electrocardiogram to substantiallyavoid detected signals other than detected signals that are recordedduring electrically quiet times.

In some embodiments, measuring the first baseline response comprisesepoch averaging of multiple epochs relative to stimulus of the nervestimulation to increase signal-to-noise ratio; measuring the secondbaseline response comprises epoch averaging of multiple epochs relativeto stimulus of the nerve stimulation to increase signal-to-noise ratio;measuring the first post-denervation response comprises epoch averagingof multiple epochs relative to stimulus of the nerve stimulation toincrease signal-to-noise ratio; and measuring the secondpost-denervation response comprises epoch averaging of multiple epochsrelative to stimulus of the nerve stimulation to increasesignal-to-noise ratio.

In specific embodiments, the nerve stimulation is multiphasicstimulation. The nerve stimulation is supplied via one or moreelectrodes made of low polarization electrode material. The nervestimulation has a narrow pulse width selected to reduce stimuluspolarization. The nerve stimulation has a pulse width substantiallyequal to chronaxie of the renal vessel.

In accordance with another aspect of the invention, a renal denervationfeedback system comprises: at least one denervation member to denervateat least some tissue proximate the renal vessel; at least onemeasurement member to perform a baseline measurement of renal nerveplexus electrical activity at a renal vessel before denervation of atleast some tissue proximate the renal vessel and to perform apost-denervation measurement of renal nerve plexus electrical activityat the renal vessel after the denervation; and a denervation assessmentmodule to assess denervation of the renal vessel based on a comparisonof the baseline measurement and the post-denervation measurement ofrenal nerve plexus electrical activity at the renal vessel.

In some embodiments, a denervation control module is configured, if atarget denervation of the renal vessel is not achieved, to instructoperation of the at least one denervation member to repeat denervatingat least some tissue proximate the renal vessel, instruct operation ofthe at least one measurement member to repeat performing apost-denervation measurement, and instruct the denervation assessmentmodule to repeat assessing denervation of the renal vessel, until thetarget denervation of the renal vessel is achieved.

These and other features and advantages of the present invention willbecome apparent to those of ordinary skill in the art in view of thefollowing detailed description of the specific embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an example of a flow diagram illustrating the renaldenervation verification and feedback method.

FIG. 2 shows an example of the renal denervation site and themeasurement site according to a first approach for assessingdenervation.

FIG. 3 shows an example of the afferent action potential and efferentaction potential.

FIG. 4 shows an example of the renal denervation site, the stimulationsite, and the measurement site according to a second approach ofassessing denervation.

FIG. 5 shows an example of assessing nerve activity by counting spikesin response to stimulation.

FIG. 6 is a schematic diagram illustrating an example of a denervationsystem with denervation verification and feedback.

FIG. 7 is a schematic diagram illustrating another example of adenervation system with denervation verification and feedback.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings which form a part of the disclosure, and in whichare shown by way of illustration, and not of limitation, exemplaryembodiments by which the invention may be practiced. In the drawings,like numerals describe substantially similar components throughout theseveral views. Further, it should be noted that while the detaileddescription provides various exemplary embodiments, as described belowand as illustrated in the drawings, the present invention is not limitedto the embodiments described and illustrated herein, but can extend toother embodiments, as would be known or as would become known to thoseskilled in the art. Reference in the specification to “one embodiment”,“this embodiment”, or “these embodiments” means that a particularfeature, structure, or characteristic described in connection with theembodiment is included in at least one embodiment of the invention, andthe appearances of these phrases in various places in the specificationare not necessarily all referring to the same embodiment. Additionally,in the following detailed description, numerous specific details are setforth in order to provide a thorough understanding of the presentinvention. However, it will be apparent to one of ordinary skill in theart that these specific details may not all be needed to practice thepresent invention. In other circumstances, well-known structures,materials, circuits, processes and interfaces have not been described indetail, and/or may be illustrated in block diagram form, so as to notunnecessarily obscure the present invention.

In the following description, relative orientation and placementterminology, such as the terms horizontal, vertical, left, right, topand bottom, is used. It will be appreciated that these terms refer torelative directions and placement in a two dimensional layout withrespect to a given orientation of the layout. For a differentorientation of the layout, different relative orientation and placementterms may be used to describe the same objects or operations.

Furthermore, some portions of the detailed description that follow arepresented in terms of algorithms, flow-charts and symbolicrepresentations of operations within a computer. These algorithmicdescriptions and symbolic representations are the means used by thoseskilled in the data processing arts to most effectively convey theessence of their innovations to others skilled in the art. An algorithmis a series of defined steps leading to a desired end state or resultwhich can be represented by a flow chart. In the present invention, thesteps carried out require physical manipulations of tangible quantitiesfor achieving a tangible result. Usually, though not necessarily, thesequantities take the form of electrical or magnetic signals orinstructions capable of being stored, transferred, combined, compared,and otherwise manipulated. It has proven convenient at times,principally for reasons of common usage, to refer to these signals asbits, values, elements, symbols, characters, terms, numbers,instructions, or the like. It should be borne in mind, however, that allof these and similar terms are to be associated with the appropriatephysical quantities and are merely convenient labels applied to thesequantities. Unless specifically stated otherwise, as apparent from thefollowing discussion, it is appreciated that throughout the description,discussions utilizing terms such as “processing,” “computing,”“calculating,” “determining,” “displaying,” or the like, can include theactions and processes of a computer system or other informationprocessing device that manipulates and transforms data represented asphysical (electronic) quantities within the computer system's registersand memories into other data similarly represented as physicalquantities within the computer system's memories or registers or otherinformation storage, transmission or display devices.

The present invention also relates to an apparatus for performing theoperations herein. This apparatus may be specially constructed for therequired purposes, or it may include one or more general-purposecomputers selectively activated or reconfigured by one or more computerprograms. Such computer programs may be stored in a computer-readablestorage medium, such as, but not limited to optical disks, magneticdisks, read-only memories, random access memories, solid state devicesand drives, or any other types of media suitable for storing electronicinformation. The algorithms and displays presented herein are notinherently related to any particular computer or other apparatus.Various general-purpose systems may be used with programs and modules inaccordance with the teachings herein, or it may prove convenient toconstruct a more specialized apparatus to perform desired method steps.In addition, the present invention is not described with reference toany particular programming language. It will be appreciated that avariety of programming languages may be used to implement the teachingsof the invention as described herein. The instructions of theprogramming language(s) may be executed by one or more processingdevices, e.g., central processing units (CPUs), processors, orcontrollers.

Exemplary embodiments of the invention, as will be described in greaterdetail below, provide apparatuses and methods for renal denervationverification and feedback.

FIG. 1 is an example of a flow diagram illustrating the renaldenervation verification and feedback method. To provide feedback duringa renal denervation procedure, the present method involves performing abaseline measurement of renal nerve plexus electrical activity at arenal vessel (step 102). The baseline measurement will be used to assessor verify the level of denervation so as to determine whether the targetdenervation is achieved or not. After performing the baselinemeasurement, at least some tissue proximate the renal vessel isdenervated (step 104). The denervating typically involves electricalstimulation such as RF ablation, but may employ other methods, includingthe application of laser, high intensity focused ultrasound (HIFU),cryoablation, other thermal mechanisms for achieving ablation, ormechanical energy to sever or interrupt conduction of the nerve fibers.After the denervating, a post-denervation measurement of renal nerveplexus electrical activity at the renal vessel is performed (step 106).Denervation of the renal vessel is assessed based on a comparison of thebaseline measurement and the post-denervation measurement of renal nerveplexus electrical activity at the renal vessel (step 108). Themeasurement may involve obtaining one or more parameters of the activityor event, such as amplitude, width, or the like, or any combinationthereof. Alternatively, the measurement may involve recording orsampling many points to reconstruct an activity or event in time.

If a target denervation of the renal vessel is not achieved, the stepsof denervating, performing a post-denervation measurement, and assessingdenervation of the renal vessel are repeated until the targetdenervation of the renal vessel is achieved (step 110). In specificembodiments, this involves adjusting a level of denervation fordenervating at least some tissue proximate the renal vessel based onresult of assessing denervation of the renal vessel. For example, the RFablation level can be adjusted based on the result of the denervationassessment.

To carry out the method, a renal denervation feedback system may includeat least one denervation member to denervate at least some tissueproximate the renal vessel, at least one measurement member to perform abaseline measurement of renal nerve plexus electrical activity at arenal vessel before denervation of at least some tissue proximate therenal vessel and to perform a post-denervation measurement of renalnerve plexus electrical activity at the renal vessel after thedenervation, and a denervation assessment module to assess denervationof the renal vessel based on a comparison of the baseline measurementand the post-denervation measurement of renal nerve plexus electricalactivity at the renal vessel. In addition, a denervation control modulemay be provided, if a target denervation of the renal vessel is notachieved, to instruct operation of the at least one denervation memberto repeat denervating at least some tissue proximate the renal vessel,instruct operation of the at least one measurement member to repeatperforming a post-denervation measurement, and instruct the denervationassessment module to repeat assessing denervation of the renal vessel,until the target denervation of the renal vessel is achieved. Repeatingthe denervating, performing a post-denervation measurement, andassessing denervation of the renal vessel may include adjusting a levelof denervation for denervating at least some tissue proximate the renalvessel based on result of assessing denervation of the renal vessel. Thedenervation assessment module and the denervation control module may beimplemented in electronic circuitry or in software or firmware forexecution by a processor, as discussed in further detail below. In thefollowing, various examples of assessing or verifying denervation of therenal vessel are presented.

First Approach

According to a first approach, performing a baseline measurementincludes monitoring baseline afferent and efferent signals at the renalvessel without external stimulation to the renal vessel, and performinga post-denervation measurement includes monitoring post-denervationafferent and efferent signals at the renal vessel without externalstimulation to the renal vessel, after the denervating.

In a specific example, this approach assesses the completeness of therenal artery denervation or ablation by measuring the renal nerve plexuselectrical activity on the distal side of the lesion site. FIG. 2 showsan example of the renal denervation site and the measurement site forassessing denervation. The measurement site 200 is distal of thedenervation site 202 and is proximal of the kidney 204. If denervationis complete, this activity will be solely afferent since efferentsignals will be blocked at the lesion site. As used herein, the“completeness” of the denervation or ablation may not require completeblockage of signals, but may indicate that a target level of denervationis reached, which can be predetermined or preset by a medicalprofessional, for instance, based on clinical data or the like.

For the baseline measurement, a baseline test is made and the distalactivity of the renal nerve plexus is recorded. This will become thebaseline measurement. After performing the denervation or ablation ofthe renal artery plexus, a post-denervation test is made and the distalactivity of the renal nerve plexus is recorded. In this example, alesion completeness score is generated, which is equal to the ratio of abaseline score (baseline measurement) and a post-denervation score(post-denervation measurement). If the lesion completeness score exceedsa predetermined threshold; then the lesion is deemed complete;otherwise, the denervation is repeated and another lesion completenessscore is generated until the predetermined threshold is met. Thepredetermined threshold can be determined in pre-clinical studies or thelike.

FIG. 3 shows an example of the afferent action potential and efferentaction potential. The action potential direction between the brain andthe kidney can be determined by looking at the morphological polarity ofthe electrogram. While both action potentials look alike as recorded onan oscilloscope, the phases are reversed polarity. The action potentialdirection can be determined by using bipolar measurement electrodes thatare organized longitudinally at the measurement site 200.

There are various ways to quantify the nerve plexus activity. In oneexample, during each nerve activity measurement period (baseline orpost-denervation), afferent and efferent “spikes” will be counted.Spikes represent compound action potential levels that meet or exceed apredetermined threshold level. The ratio of the number of afferentspikes and the number of efferent spikes will be computed for bothperiods and assigned as the lesion completeness score. That is,monitoring the baseline afferent signals and baseline efferent signalsincludes monitoring baseline afferent compound action potential andbaseline efferent compound action potential, counting a number ofbaseline afferent spikes each representing an afferent compound actionpotential that exceeds a preset threshold during a specified period oftime, and counting a number of baseline efferent spikes eachrepresenting an efferent compound action potential that exceeds thepreset threshold during the specified period of time. Monitoring thepost-denervation afferent signals and post-denervation efferent signalsincludes monitoring post-denervation afferent compound action potentialand post-denervation efferent compound action potential, counting anumber of post-denervation afferent spikes each representing an afferentcompound action potential that exceeds the preset threshold during thespecified period of time, and counting a number of post-denervationefferent spikes each representing an efferent compound action potentialthat exceeds the preset threshold during the specified period of time.

In one specific embodiment, the baseline measurement and thepost-denervation measurement occur at a location of the renal vesselproximal of a kidney and distal of a denervation location fordenervating at least some tissue proximate the renal vessel (as seen inFIG. 2). The target denervation of the renal vessel is achieved when aratio of the number of post-denervation afferent spikes to the number ofpost-denervation efferent spikes is above a preset threshold as comparedto a ratio of the number of baseline afferent spikes to the number ofbaseline efferent spikes.

In another specific embodiment, the baseline measurement and thepost-denervation measurement occur at a location of the renal vesselproximal of a kidney and proximal of a denervation location fordenervating at least some tissue proximate the renal vessel (e.g., byswapping the measurement site 200 and the denervation site 202 in FIG.2). The target denervation of the renal vessel is achieved when a ratioof the number of post-denervation afferent spikes to the number ofpost-denervation efferent spikes is below a preset threshold as comparedto a ratio of the number of baseline afferent spikes to the number ofbaseline efferent spikes.

Second Approach

According to a second approach, performing a baseline measurementincludes supplying nerve stimulation to the renal vessel from one sideof a denervation location for denervating at least some tissue proximatethe renal vessel and measuring a baseline response of the renal vesselto the nerve stimulation on an opposite side of the denervationlocation, and performing a post-denervation measurement includessupplying nerve stimulation to the renal vessel from one side of thedenervation location and measuring a post-denervation response of therenal vessel to the nerve stimulation on an opposite side of thedenervation location. Examples of nerve stimulation include electricalstimulation and pharmacological stimulation such as the injection ofneurotoxins.

In a specific example, the method assesses the completeness of the renalartery denervation or ablation by stimulating the renal nerve plexus onthe proximal side of the lesion while measuring the renal nerve plexusactivity on the distal side of the lesion. FIG. 4 shows an example ofthe renal denervation site, the stimulation site, and the measurementsite according to the second approach of assessing denervation. Thestimulation site 400 is proximal of the denervation site 402, and themeasurement site 404 is distal of the denervation site 402 and isproximal of the kidney 406. Before the denervation, a baseline test ismade by stimulating the renal artery plexus and simultaneously measuringthe distal activity. This will become the baseline measurement. Afterperform the denervation or ablation of the renal artery plexus, apost-denervation test is made by stimulating the renal artery plexus andsimultaneously measuring the distal activity to obtain thepost-denervation measurement. A lesion completeness score is generatedas the ratio of the baseline score (baseline measurement) and thepost-denervation score (post-denervation measurement). If the lesioncompleteness score exceeds a predetermined threshold, then the lesion iscomplete; otherwise, the denervation is repeated and another lesioncompleteness score is generated until the predetermined threshold ismet. The predetermined threshold can be determined in pre-clinicalstudies or the like.

In one specific embodiment, the same nerve stimulation is supplied fromthe same first location on the same side of the denervation location forboth the baseline measurement and the post-denervation measurement, andthe response is recorded on the same second location on the sameopposite side of the denervation location for both the baselinemeasurement and the post-denervation measurement (as seen in FIG. 4).

In another specific embodiment, the nerve stimulation is supplied fromthe proximal side of the denervation location for both the baselinemeasurement and the post-denervation measurement, and the response isrecorded on the distal side of the denervation location for both thebaseline measurement and the post-denervation measurement (as seen inFIG. 4).

Assessing denervation of the vessel includes computing a baselineparameter from the baseline response, computing a post-denervationparameter from the post-denervation response, and computing a degree ofdenervation as a ratio of the post-denervation parameter and thebaseline parameter. The target denervation is achieved when the computedratio falls within a preset range.

There are various ways to quantify the nerve plexus activity. One way ofassessing nerve activity is to count what are known as “spikes” during aspecified period of time. Spikes represent compound action potentiallevels that meet or exceed a predetermined threshold level. FIG. 5 showsan example of assessing nerve activity by counting spikes in response tostimulation. The first recorded activity for the baseline measurementshows a number of spikes in response to the stimulation. The secondrecorded activity for the post-denervation measurement shows little orno spikes in response to the stimulation for a successful denervation,for which stimulation is not conducted or at least substantially notconducted after the denervating. The third recorded activity for thepost-denervation measurement shows spikes in response to the stimulationfor an unsuccessful denervation, for which stimulation is stillconducted after the denervating.

In one example, the baseline parameter includes a number of baselinespikes each representing a compound action potential that exceeds apreset threshold during a specified period of time as measured in thebaseline response. The post-denervation parameter includes a number ofpost-denervation spikes each representing a compound action potentialthat exceeds the same preset threshold during the same specified periodof time as measured in the post-denervation response. The targetdenervation is achieved when the computed ratio falls below a presetnumber. The preset number can be determined by clinical studies or thelike.

Third Approach

According to a third approach, performing a baseline measurementincludes supplying nerve stimulation to the renal vessel from a firstside of a denervation location for denervating at least some tissueproximate the renal vessel and measuring a first baseline response ofthe renal vessel to the nerve stimulation on a second side of thedenervation location opposite the first side, and supplying nervestimulation to the renal vessel from the second side and measuring asecond baseline response of the renal vessel to the nerve stimulation onthe first side, and performing a post-denervation measurement includessupplying nerve stimulation to the renal vessel from the first side andmeasuring a first post-denervation response of the renal vessel to thenerve stimulation on the second side, and supplying nerve stimulation tothe renal vessel from the second side and measuring a secondpost-denervation response of the renal vessel to the nerve stimulationon the first side.

Referring to FIG. 4, the stimulation site 400 is on the proximal side(first side) of the denervation site 402, and the measurement site 404is on the distal side (second side) of the denervation site 402. Thisconfiguration is used to record the first response (baseline orpost-denervation). To record the second response (baseline orpost-denervation), the stimulation site 400 and the measurement site 404are swapped to opposite sides from the configuration shown in FIG. 4.According to the third approach, denervation verification test in bothefferent and afferent directions is used to verify complete,bidirectional denervation.

In a specific embodiment, performing a baseline measurement includessupplying nerve stimulation to the renal vessel from a first location onthe first side of the denervation location and measuring the firstbaseline response of the renal vessel to the nerve stimulation on asecond location on the second side, and supplying nerve stimulation tothe renal vessel from the second location and measuring the secondbaseline response of the renal vessel to the nerve stimulation at thefirst location. Performing a post-denervation measurement includessupplying nerve. stimulation to the renal vessel from the first locationand measuring the first post-denervation response of the renal vessel tothe nerve stimulation at the second location, and supplying nervestimulation to the renal vessel from the second location and measuringthe second post-denervation response of the renal vessel to the nervestimulation at the first location.

The heart and other muscles of the body generate noise that caninterfere with subject verification. Various signal processing methodscan be used to increase the signal-to-noise ratio of the detected signal(DS) resulting from the verification test stimulus. Measuring the firstbaseline response includes filtering the first baseline response toincrease signal-to-noise ratio. Measuring the second baseline responseincludes filtering the second baseline response to increasesignal-to-noise ratio. Measuring the first post-denervation responseincludes filtering the first baseline response to increasesignal-to-noise ratio. Measuring the second post-denervation responseincludes filtering the second baseline response to increasesignal-to-noise ratio. Various filtering techniques can be used,including the use of a band pass filter to filter out EKG noise andother background noise from the patient and the surroundings. In oneexample, a band pass filter in the range of about 500 to about 5,000 orup to about 10,000 Hz may be used.

One technique to improve signal-to-noise involves synchronizing themeasurement with the electrocardiogram to include only DS signals thatare recorded during electrically quiet times (e.g., ST segment).Cardiosynchronous processing of denervation test signals reduces theeffect of cardiogenic noise. Denervation test signal epoch averaging ofN epochs is used to improve signal-to-noise by TN. For instance, signalaveraging of 400 signal epochs can improve signal-to-noise by a factorof 20. Measuring the first baseline response, measuring the secondbaseline response, measuring the first post-denervation response, andmeasuring the second post-denervation response each includesynchronizing with electrocardiogram to substantially avoid detectedsignals other than detected signals that are recorded duringelectrically quiet times. For example, measuring the first baselineresponse, measuring the second baseline response, measuring the firstpost-denervation response, and measuring the second post-denervationresponse each include epoch averaging of multiple epochs relative tostimulus of the nerve stimulation to increase signal-to-noise ratio. Theabove filters are used to improve denervation test detectedsignal-to-noise ratio to improve the confidence of denervationverification.

Another feature is to limit the effect of stimulus polarization on themeasurement. Since neural pulses travel many meters per second, it isnecessary to sense the evoked neural response within microseconds afterthe stimulus. Polarization afterpotentials are minimized by using abipolar or quadpolar or pentapolar stimulation pulse that has no DCcontent and tends to rapidly neutralize polarization effects.

In certain preferred embodiments, the nerve stimulation is multiphasicstimulation. Multiphasic stimuli tend to have little polarizationafterpotential. The nerve stimulation is supplied via one or moreelectrodes made of low polarization electrode material. Low polarizationstimulation electrodes are used to minimize polarizationafterpotentials. Examples include Ag/AgCl, TiN, IrOx, and platinizedplatinum. For a discussion of identifying stimulus parameters andelectrode geometries that were effective in selectively stimulatingtargeted neuronal populations within the central nervous system, seeCameron C. McIntyre & Warren M. Grill, “Selective Microstimulation ofCentral Nervous System Neurons,” Annals of Biomedical Engineering. 2000;28:219-233.

The nerve stimulation has a narrow pulse width selected to reduce orminimize stimulus polarization (e.g., about 50 microseconds). In onespecific embodiment, the nerve stimulation has a pulse widthsubstantially equal to chronaxie of the renal vessel. Chronaxie is thetissue-excitability parameter that permits choice of the optimumstimulus pulse duration for stimulation of any excitable tissue. Whenthe chronaxie of nerve is measured, it is important to recognize thatmost nerve trunks contain bundles of fibers having different diametersand hence different propagation velocities, and with each fiber grouphaving its own chronaxie. A strength-duration curve can be plotted foreach fiber group, from which the chronaxies can be determined. SeeLeslie A. Geddes, “Accuracy Limitations of Chronaxie Values,” IEEETransactions on Biomedical Engineering. January 2004; 51(1):176-181.

Exemplary Systems

FIG. 6 is a schematic diagram illustrating an example of a denervationsystem with denervation verification and feedback. A renal vessel 600may include efferent nerves for efferent conduction and/or afferentnerves for afferent in the directions shown. Note that when a nerve isstimulated, it will conduct in both directions regardless of whether thenerve is efferent or afferent. Therefore, one may characterize onedirection of conduction as orthodromic (e.g., in the normal directionfor that nerve) instead of efferent and the opposite direction ofconduction as antidromic (e.g., in the direction opposite the normaldirection for that nerve) instead of afferent.

In FIG. 6, a pair of stimulating electrodes 602 are provided tostimulate efferent nerves or nerves for orthodromic and efferentconduction (e.g., with the stimulus as shown) under the control of aprocessor 604 via a D/A converter 606, and another pair of detecting ormeasurement electrodes 608 are provided to record nerve plexuselectrical activity to determine whether there is orthodromic orefferent conduction. The measurement electrodes 608 are coupled via anamplifier 610 (e.g., having a 10⁵ gain), a band pass filter or BPF 612(e.g., about 500-10,000 Hz), and an ND converter 614 to the processor604. The processor 604 has circuitries and/or executes software modulesstored in memory 620 in order to control the nerve stimulating andmeasuring and to control operation of a denervation apparatus 624 fordenervating at least some tissue proximate the renal vessel 600 at alocation between the stimulating electrodes 602 and the measurementelectrodes 608 (e.g., in the form of ablation electrodes on the nerves).The denervation apparatus 624 may include, for example, a denervationmember in the form of one or more RF electrodes and an RF energy source.For illustrative purposes, FIG. 6 shows a denervation assessment module626 to assess denervation of the renal vessel based on a comparison ofthe baseline measurement and the post-denervation measurement of renalnerve plexus electrical activity at the renal vessel 600 and adenervation control module 628 to control the nerve denervation by thedenervation apparatus 624. If a target denervation of the renal vessel600 is not achieved, the denervation control module 628 instructsoperation of the denervation apparatus 624 to repeat denervating atleast some tissue proximate the renal vessel, instructs operation of themeasurement electrodes 608 to repeat performing a post-denervationmeasurement, and instructs the denervation assessment module 626 torepeat assessing denervation of the renal vessel 600, until the targetdenervation of the renal vessel 600 is achieved.

The denervation system in FIG. 6 can be used to carry out the procedureof the first approach (without activating the stimulating electrodes602), the procedure of the second approach, and partially the procedureof the third approach (with the need to swap the stimulating andmeasuring positions). A denervation system that is more suitable for thethird approach is shown in FIG. 7.

It will be understood by those of ordinary skill in the art that thevarious methods and systems described herein can be performed eitherintravascularly, extravascularly, or a combination approach using bothintravascular and extravascular approaches in combination. In theintravascular approach, a suitable ablation catheter is advanced throughthe patient's vasculature and into the renal artery adjacent theafferent and efferent renal nerves.

FIG. 7 is a schematic diagram illustrating another example of adenervation system with denervation verification and feedback. A renalvessel 700 has coupled thereto a plurality of electrodes 701-706. FIG. 7shows a 6-electrode system, but the number of electrodes can vary inother embodiments. In FIG. 7, all six electrodes are used for ablation,while two pairs of electrodes 701-702 and 705-706 are alternately usedfor stimulating and measuring to perform denervation verification.Denervation by ablation is performed by connecting an RF amplifier 710via leads to the six electrodes 701-706 in sequence using six switches711-716 which are connected to the output of the RF amplifier 710 and anRF oscillator 718 and controlled by a computer or controller 720. Thecomputer 720 has a processor, a memory, and various circuitries andmodules to control denervation of the renal vessel 700 and performdenervation verification and feedback, including pulse generation,signal control, switch control, filtering, signal averaging, etc. Forexample, the computer 720 may include a denervation assessment moduleand a denervation control module such as those shown in FIG. 6.

After ablation, inactivation of the renal nerves of the renal vessel 700is verified by stimulating a pair of electrodes 701-702 or 705-706(bipolarly or unipolarly), alternately, using D/A converters 733, 734and switches connected to their outputs (pairs of switches correspondingto pairs of stimulating electrodes 701-702 and 705-706), and by“listening” for a conducted signal by selecting a pair of electrodes705-706 or 701-702, alternately, to connect to a measurement amplifier740 via switches (pairs of switches corresponding to pairs ofmeasurement electrodes 705-706 and 701-702). The measurement amplifier740 is connected to an analog or digital band pass filter or BPF 746 ordirectly to an ND converter 748 that is read by the computer 720. TheBPF 746 can be eliminated if such filtering is done in the computer 720.A control panel for the system may include user controls 752 and display754. According to the third approach, the denervation assessment modulein the computer 720 contains an algorithm to analyze the response “seen”by the measurement amplifier 740 and decides if the renal nerves areblocked and the stimulation/response verification can be performed ondifferent electrodes to assure all nerves are blocked. If more ablationis needed, the denervation control module in the computer 720 can advisethe user or perform additional ablation automatically until there is noafferent or efferent nerve signal continuity.

In the description, numerous details are set forth for purposes ofexplanation in order to provide a thorough understanding of the presentinvention. However, it will be apparent to one skilled in the art thatnot all of these specific details are required in order to practice thepresent invention. It is also noted that the invention may be describedas a process, which is usually depicted as a flowchart, a flow diagram,a structure diagram, or a block diagram. Although a flowchart maydescribe the operations as a sequential process, many of the operationscan be performed in parallel or concurrently. In addition, the order ofthe operations may be re-arranged.

From the foregoing, it will be apparent that the invention providesmethods, apparatuses and programs stored on computer readable media forrenal denervation verification and feedback. Additionally, whilespecific embodiments have been illustrated and described in thisspecification, those of ordinary skill in the art appreciate that anyarrangement that is calculated to achieve the same purpose may besubstituted for the specific embodiments disclosed. This disclosure isintended to cover any and all adaptations or variations of the presentinvention, and it is to be understood that the terms used in thefollowing claims should not be construed to limit the invention to thespecific embodiments disclosed in the specification. Rather, the scopeof the invention is to be determined entirely by the following claims,which are to be construed in accordance with the established doctrinesof claim interpretation, along with the full range of equivalents towhich such claims are entitled.

1-25. (canceled)
 26. A renal denervation feedback method comprising:performing a baseline measurement of intrinsic renal nerve plexuselectrical activity at a renal vessel by monitoring compound actionpotentials including baseline afferent and efferent signals; denervatingat least some tissue proximate the renal vessel after performing thebaseline measurement; performing a post-denervation measurement ofintrinsic renal nerve plexus electrical activity at the renal vessel bymonitoring post-denervation compound action potentials includingpost-denervation afferent and efferent signals, after the denervating;assessing denervation of the renal vessel based on a comparison of thebaseline measurement and the post-denervation measurement of renal nerveplexus electrical activity at the renal vessel; and determining thedenervation is complete when the post-denervation compound actionpotentials include afferent signals below a threshold value.
 27. Therenal denervation feedback method of claim 26, further comprising, ifthe denervation is not complete: repeating the steps of denervating,performing a post-denervation measurement, and assessing denervation ofthe renal vessel until the post-denervation compound action potentialsare solely efferent signals.
 28. The renal denervation feedback methodof claim 27, wherein repeating the steps of denervating, performing apost-denervation measurement, and assessing denervation of the renalvessel comprises: adjusting a level of denervation for denervating atleast some tissue proximate the renal vessel based on a result ofassessing denervation of the renal vessel.
 29. The renal denervationfeedback method of claim 26, wherein performing the baseline measurementof renal nerve plexus electrical activity comprises: counting a numberof baseline afferent spikes each representing an afferent compoundaction potential that exceeds a preset threshold during a specifiedperiod of time; and counting a number of baseline efferent spikes eachrepresenting an efferent compound action potential that exceeds thepreset threshold during the specified period of time, and whereinperforming a post-denervation measurement of renal nerve plexuselectrical activity comprises: counting a number of post-denervationafferent spikes each representing an afferent compound action potentialthat exceeds the preset threshold during the specified period of time;and counting a number of post-denervation efferent spikes eachrepresenting an efferent compound action potential that exceeds thepreset threshold during the specified period of time.
 30. The renaldenervation feedback method of claim 26, wherein performing a baselinemeasurement comprises supplying nerve stimulation to the renal vesselfrom one side of a denervation location for denervating at least sometissue proximate the renal vessel and measuring a baseline response ofthe renal vessel to the nerve stimulation on an opposite side of thedenervation location; and wherein performing a post-denervationmeasurement comprises supplying nerve stimulation to the renal vesselfrom one side of the denervation location and measuring apost-denervation response of the renal vessel to the nerve stimulationon an opposite side of the denervation location.
 31. The renaldenervation feedback method of claim 26, wherein monitoring compoundaction potentials including baseline afferent and efferent signalscomprises using a plurality of bi-polar measurement electrodes tomeasure the baseline afferent and efferent signals.
 32. The renaldenervation feedback method of claim 26, wherein monitoring compoundaction potentials including post-denervation afferent and efferentsignals comprises using a plurality of bi-polar measurement electrodesto measure the post-denervation afferent and efferent signals.
 33. Therenal denervation feedback method of claim 26, wherein denervating atleast some tissue proximate the renal vessel after performing thebaseline measurement comprises using at least one denervation electrodeto denervate the at least some tissue.
 34. A renal denervation feedbacksystem comprising: at least one denervation member to denervate at leastsome tissue proximate the renal vessel; at least one measurement memberto perform a baseline measurement of intrinsic renal nerve plexuselectrical activity, including baseline afferent and efferent signals,at a renal vessel before denervation of at least some tissue proximatethe renal vessel and to perform a post-denervation measurement of renalnerve plexus electrical activity, including post-denervation afferentand efferent signals, at the renal vessel after the denervation, thebaseline and post-denervation measurements acquired by monitoringcompound action potentials; and a denervation assessment module toassess denervation of the renal vessel based on a comparison of thebaseline measurement and the post-denervation measurement of renal nerveplexus electrical activity at the renal vessel, wherein the denervationassessment module is configured to determine the denervation is completewhen the post-denervation compound action potentials include afferentsignals below a threshold value.
 35. The renal denervation system ofclaim 34, wherein, if the denervation is not complete, the denervationassessment module is further configured to direct the at least onedenervation member to repeat denervation of the at least some tissue.36. The renal denervation system of claim 35, wherein the denervationassessment module is further configured to direct the at least onedenervation member to adjust a level of denervation for denervating theat least some tissue proximate the renal vessel.
 37. The renaldenervation system of claim 34, wherein the at least one measurementmember is configured to perform the baseline measurement of renal nerveplexus electrical activity by: counting a number of baseline afferentspikes each representing an afferent compound action potential thatexceeds a preset threshold during a specified period of time; andcounting a number of baseline efferent spikes each representing anefferent compound action potential that exceeds the preset thresholdduring the specified period of time, and wherein the at least onemeasurement member is configured to perform the post-denervationmeasurement of renal nerve plexus electrical activity by: counting anumber of post-denervation afferent spikes each representing an afferentcompound action potential that exceeds the preset threshold during thespecified period of time; and counting a number of post-denervationefferent spikes each representing an efferent compound action potentialthat exceeds the preset threshold during the specified period of time.38. The renal denervation feedback system of claim 34, wherein the atleast one measurement member comprises a plurality of bi-polarmeasurement electrodes.
 39. The renal denervation feedback system ofclaim 34, wherein the at least one denervation member comprises at leastone denervation electrode.